The dystrophin glycoprotein complex is a specialized complex of cardiac and skeletal muscle. The function of the dystrophin glycoprotein complex is not fully understood, but it appears to stabilize the plasma membrane of skeletal and cardiac muscle and serve in a mechanosignaling capacity. Defects in the dystrophin glycoprotein complex lead to skeletal muscle dystrophy and cardiomyopathy in both human patients and mouse models. We previously engineered mouse models lacking gamma-sarcoglycan or delta-sarcoglycan and found that these mice effectively model the human disorder. In mice, as in humans with dystrophin-glycoprotein complex gene defects, there is variability in the phenotypic outcome. We hypothesize that aspects of this phenotypic variability is under genetic control. We now propose to identify new genes and to test existing genes for their ability to modulate the phenotype from sarcoglycan gene mutations. We now show that the genetic background influences two different quantitative features of muscular dystrophy. The degree of fibrosis and the degree of membrane permeability both significantly vary in gamma sarcoglycan null mice related to the specific genetic background. We propose to map these quantitative traits to determine the genetic modifier loci that affect the phenotypic outcome in muscular dystrophy. Genetic modifier genes are useful since they may aid in counseling subjects with muscular dystrophy as well as lead to new avenues of therapy. We will study to additional genetic backgrounds for their ability to suppress the muscular dystrophy and cardiomyopathy phenotypes in gamma sarcoglycan null mice. We show now that defects in the major integrin complex of skeletal muscle lead to a profound muscular dystrophy phenotype with enhanced skeletal muscle degeneration and early lethality. Therefore, we will investigate the cellular and molecular effects of integrin as a modifier of the muscular dystrophy phenotype. Lastly, endothelial nitric oxide synthase will be studied as a modifier of the cardiomyopathic features of limb girdle muscular dystrophy using genetic and pharmacologic approaches. These findings will improve our understanding of the cellular defects in muscular dystrophy and cardiomyopathy and may help devise new strategies for therapy.